Disease Management of ADHD and Measures of Compliance

Disease Management of ADHD and Measures of Compliance Imagine living in a fast-moving kaleidoscope, where sounds, images, and thoughts are constantly shifting—feeling easily bored, yet helpless to keep your mind on tasks you need to complete, distracted by unimportant sights and sounds, your mind drives you from one thought or activity to the next—perhaps you are so wrapped up in a collage of thoughts and images that you don’t notice when someone speaks to you. This is how the National Institutes of Health introduces the term “attentiondeficit/hyperactivity disorder” (ADHD). People with ADHD may show several signs of being consistently inattentive, or they may have a pattern of being hyperactive and impulsive, or they may exhibit all 3 types of behavior. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the signs of inattention include (a) becoming easily distracted by irrelevant sights and sounds, (b) failing to pay attention to details and making careless mistakes, (c) rarely following instructions carefully and completely, or (d) losing or forgetting things like toys, or pencils, books, and tools needed for a task. The signs for hyperactivity and impulsivity may include (a) feeling restless, often fidgeting with hands or feet, or squirming; (b) running, climbing, or leaving a seat, in situations where sitting or quiet behavior is expected; (c) blurting out answers before hearing the whole question; or (d) having difficulty waiting in line or for a turn. The diagnostic criteria for ADHD in children require 6 elements: (1) the symptoms of inattention or impulsivity or hyperactivity persist for a period of at least 6 months to a degree that is maladaptive and immature; (2) the symptoms begin before the age of 7; (3) the symptoms must be present in at least 2 types of situations, such as school, work, or home; (4) the disorder impairs school, social, or occupational functioning; (5) the symptoms do not occur solely during a pervasive developmental disorder or any psychotic disorder including schizophrenia; and (6) the symptoms are not explained better by a mood, anxiety, dissociative or personality disorder. The diagnosis of ADHD depends primarily upon symptoms of inattention or hyperactivity-impulsivity. For ADHD associated with inattention (ICD-9-CM 314.00), the patient must have at least 6 of the following 9 criteria: • Fails to pay close attention to details or makes careless errors in schoolwork, work or other activities • Has trouble keeping attention on tasks or play • Doesn’t appear to listen when being told something • Neither follows through on instructions nor completes chores, schoolwork, or jobs (not due to oppositional behavior or failure to understand) • Has trouble organizing activities and tasks • Dislikes or avoids tasks that involve sustained mental effort (homework, schoolwork) • Loses materials needed for activities (assignments, books, pencils, tools, toys) • Is easily distracted by extraneous stimuli • Is forgetful Hyperactivity or impulsivity is the second category of symptoms used to make a diagnosis of ADHD. The ADHD patient must have at least 6 of the following 9 criteria to warrant the ICD-9-CM code 314.01 (the last 3 criteria are associated with impulsivity): • Squirms in seat or fidgets • Inappropriately leaves seat • Inappropriately runs or climbs (in adolescents or adults, this may be only a subjective feeling of restlessness) • Has trouble quietly playing or engaging in leisure activity • Appears driven or “on the go” • Talks excessively • Answers questions before they have been completely asked • Has trouble waiting in line or awaiting turn • Interrupts or intrudes on others While pharmacotherapy is often effective in ADHD, the relative effectiveness depends upon the measure. The ultimate measures of effectiveness in managing ADHD are social performance, scholastic performance for children and most young adults, or work performance for others. By these measures, pharmacotherapy is secondary to social-environmental changes to encourage better scholastic performance for children, such as parents spending time with their children on homework assignments or the use of tutors. Second-line therapy might involve the assistance of professional educators, counselors, psychologists, school personnel, community mental health therapists, or the primary care clinician. However, the medicalization of ADHD brings with it the tendency to skip first-line and secondline interventions and jump to third-line intervention with pharmacotherapy. For some ADHD patients, drug therapy is necessary and effective. However, the extent of compliance with pharmacotherapy to achieve the desired outcomes would appear to be a separate consideration. For children and adolescents, clinicians may use drug-free holidays to affirm the continued value of the drug therapy in the social environment outside of school, and national guidelines focus upon behavioral measures of disease management success such as improved academic performance and improvements in relationships with parents, siblings, teachers, and peers. These evidence-based guidelines state that if there is a need for relief of symptoms of ADHD only during school, a 5-day dose schedule may be sufficient. As suggested above, there is also the matter of uncertainty in diagnosis of ADHD. Diagnosis of ADHD is not easy because its symptoms may be manifest in other conditions such as oppositional defiant disorder, found in nearly one half of ADHD children, mostly boys. ADHD can be confused with other conditions such as underachievement at school due to a learning disability, attention lapses caused by petit mal seizures, a middle ear infection that causes an intermittent hearing problem, or disruptive or unresponsive behavior due to anxiety or depression. In this issue of the Journal, Perwien, Hall, Swensen, and


II Disease Management of ADHD and Measures of Compliance
Imagine living in a fast-moving kaleidoscope, where sounds, images, and thoughts are constantly shifting-feeling easily bored, yet helpless to keep your mind on tasks you need to complete, distracted by unimportant sights and sounds, your mind drives you from one thought or activity to the next-perhaps you are so wrapped up in a collage of thoughts and images that you don't notice when someone speaks to you. This is how the National Institutes of Health introduces the term "attentiondeficit/hyperactivity disorder" (ADHD). 1 People with ADHD may show several signs of being consistently inattentive, or they may have a pattern of being hyperactive and impulsive, or they may exhibit all 3 types of behavior.
According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the signs of inattention include (a) becoming easily distracted by irrelevant sights and sounds, (b) failing to pay attention to details and making careless mistakes, (c) rarely following instructions carefully and completely, or (d) losing or forgetting things like toys, or pencils, books, and tools needed for a task. 2 The signs for hyperactivity and impulsivity may include (a) feeling restless, often fidgeting with hands or feet, or squirming; (b) running, climbing, or leaving a seat, in situations where sitting or quiet behavior is expected; (c) blurting out answers before hearing the whole question; or (d) having difficulty waiting in line or for a turn.
The diagnostic criteria for ADHD in children require 6 elements: (1) the symptoms of inattention or impulsivity or hyperactivity persist for a period of at least 6 months to a degree that is maladaptive and immature; (2) the symptoms begin before the age of 7; (3) the symptoms must be present in at least 2 types of situations, such as school, work, or home; (4) the disorder impairs school, social, or occupational functioning; (5) the symptoms do not occur solely during a pervasive developmental disorder or any psychotic disorder including schizophrenia; and (6) the symptoms are not explained better by a mood, anxiety, dissociative or personality disorder. 3 The diagnosis of ADHD depends primarily upon symptoms of inattention or hyperactivity-impulsivity. For ADHD associated with inattention (ICD-9-CM 314.00), the patient must have at least 6 of the following 9 criteria: • Fails to pay close attention to details or makes careless errors in schoolwork, work or other activities • Has trouble keeping attention on tasks or play • Doesn't appear to listen when being told something • Neither follows through on instructions nor completes chores, schoolwork, or jobs (not due to oppositional behavior or failure to understand) • Has trouble organizing activities and tasks • Dislikes or avoids tasks that involve sustained mental effort (homework, schoolwork) • Loses materials needed for activities (assignments, books, pencils, tools, toys) • Is easily distracted by extraneous stimuli

• Is forgetful
Hyperactivity or impulsivity is the second category of symptoms used to make a diagnosis of ADHD. The ADHD patient must have at least 6 of the following 9 criteria to warrant the ICD-9-CM code 314.01 (the last 3 criteria are associated with impulsivity): • Squirms in seat or fidgets • Inappropriately leaves seat • Inappropriately runs or climbs (in adolescents or adults, this may be only a subjective feeling of restlessness) • Has trouble quietly playing or engaging in leisure activity • Appears driven or "on the go" • Talks excessively • Answers questions before they have been completely asked • Has trouble waiting in line or awaiting turn • Interrupts or intrudes on others While pharmacotherapy is often effective in ADHD, the relative effectiveness depends upon the measure. The ultimate measures of effectiveness in managing ADHD are social performance, scholastic performance for children and most young adults, or work performance for others. By these measures, pharmacotherapy is secondary to social-environmental changes to encourage better scholastic performance for children, such as parents spending time with their children on homework assignments or the use of tutors. Second-line therapy might involve the assistance of professional educators, counselors, psychologists, school personnel, community mental health therapists, or the primary care clinician. However, the medicalization of ADHD brings with it the tendency to skip first-line and secondline interventions and jump to third-line intervention with pharmacotherapy.
For some ADHD patients, drug therapy is necessary and effective. However, the extent of compliance with pharmacotherapy to achieve the desired outcomes would appear to be a separate consideration. For children and adolescents, clinicians may use drug-free holidays to affirm the continued value of the drug therapy in the social environment outside of school, 4 and national guidelines focus upon behavioral measures of disease management success such as improved academic performance and improvements in relationships with parents, siblings, teachers, and peers. 5 These evidence-based guidelines state that if there is a need for relief of symptoms of ADHD only during school, a 5-day dose schedule may be sufficient.
As suggested above, there is also the matter of uncertainty in diagnosis of ADHD. Diagnosis of ADHD is not easy because its symptoms may be manifest in other conditions such as oppositional defiant disorder, found in nearly one half of ADHD children, mostly boys. ADHD can be confused with other conditions such as underachievement at school due to a learning disability, attention lapses caused by petit mal seizures, a middle ear infection that causes an intermittent hearing problem, or disruptive or unresponsive behavior due to anxiety or depression. 1 In this issue of the Journal, Perwien, Hall, Swensen, and Swindle find that compliance with pharmacotherapy for ADHD is imperfect. 6 However, the authors use a rigorous measure of compliance that may overstate the problem. By their measure, a patient who refilled an ADHD prescription at 38 days after receiving a prescription of a 30-day supply would be deemed noncompliant with therapy. Drug-free "holidays" are commonly prescribed by physicians for patients with ADHD, particularly children and adolescents. The patient who refills the 30-day prescription at 38 days may, in fact, be compliant with physician instructions and yet be deemed noncompliant by the measure used by Perwien, Hall, Swensen, and Swindle. However, this study does shed additional light on the manner in which ADHD pharmacotherapy is actually used in members of 6 MCO health plans who had at least 1 medical visit that was coded with a primary or secondary diagnosis code of either ICD-9-CM 314.00 or 314.01.

II Clinical Pharmacist Interventions to Bridge the Quality Chasm and Methods Necessary to Hold Quality Improvement Gains
The Study of Cardiovascular Risk Intervention by Pharmacists showed that the primary end point, a composite measure of improvement in the course of cholesterol risk management, was attained in 196 intervention patients (57%) compared with 102 control patients (31%). The study was stopped early due to the significant difference in the outcomes between the treatment group and the control group. The study randomized 673 patients at high risk for cardiovascular events who had atherosclerosis or diabetes with another risk factor, regardless of their cholesterol level, into the pharmacist intervention group in which they received education and a brochure on risk factors, point-ofcare cholesterol management, referral to their physician, and follow-up. Follow-up occurred for each patient every 2 to 4 weeks for 16 weeks. The physician of each patient in the intervention group also received an information sheet by fax on the risk factors of the patient and any treatment suggestions. The secondary end point, measurement of a fasting cholesterol panel performed by the primary care physician, was reached in 53% of intervention patients but in only 29% of controls. 7 An update in 2002 on the subject of measuring the value of clinical pharmacist interventions focused on the need for rigorous research designs that include a control group and randomization of patients, whenever possible. 8 In this subject review, Malone cited the design and results of the IMPROVE study that enrolled 1,054 patients from 9 Veteran Affairs (VA) medical centers and randomized 523 subjects to ambulatory clinical pharmacy services plus usual medical care and 531 subjects to usual medical care only. There were no differences found in SF-36 scores or patient satisfaction 9 or in the measure of overall resource utilization. 10 By a fourth measure, reduction in total cholesterol (TC) and low-density lipoprotein (LDL), the pharmacy intervention group showed statistically greater reductions compared with the control group. Since both groups showed reductions in LDL and TC, the inclusion of a control group permitted attribution of the LDL and TC reductions to the pharmacist intervention rather than to other factors such as system-wide cholesterol reduction efforts. The IMPROVE study also found that total medical care costs were not greater in the pharmacist intervention group, demonstrating improved efficiency; i.e., improved patient outcomes (reduction in TC and LDL) at the same cost.
Other less rigorous study designs nevertheless produced information about the nature of interventions commonly performed by community pharmacists in routine practice. For example, a 4-week study performed in 1996 in 28 community (rural and urban) pharmacies found 1,487 documented interventions, an average of 53.1 interventions per pharmacy per week or about 2 interventions per pharmacy per day. A total of 1,223 interventions (82%) could be attributed to a specific action: 29% (351) involved actions related to prescribing errors, of which 60% were found to be associated with inappropriate dose, regimen, or strength; 28% (342) related to drug therapy monitoring (the most common reasons were side effects, toxicity, allergic reactions, and patients' concerns and questions); 24% (299) were prescription omission interventions, of which form-strength not specified or unavailable was the most common (34%); and 19% (231) were related to drug interaction interventions, of which drug-drug and allergy-sensitivity were the most common. 11 Outside of randomized control group trials, there are reports of local programs and projects that have demonstrated favorable effects of community pharmacist interventions. In one of the longest-running demonstration projects, the city of Asheville, North Carolina, began paying community pharmacists in 1997 to counsel diabetic beneficiaries in diet, nutrition, exercise, and glycemic control in the hope of reducing complications of the disease. 12 The diabetes management program began as a 6-month pilot project, but initial results, including favorable opinions from beneficiaries, resulted in retention and expansion of the "Asheville Project." Five years later, the Asheville Project involved the 3 large employers in the areathe hospital, the City of Asheville, and a paper company-and community pharmacists were being compensated for clinical interventions in hypertension, asthma, and hypercholesterolemia as well as diabetes. Anecdotes from patients attributed behavior changes in regular walking, strict attention to glucose monitoring, daily aspirin use, and better asthma control and use of fewer inhalers to regular pharmacist counseling. As one retired Asheville city employee said, the Asheville Project using community pharmacists "gives you the knowledge, the equipment, and the incentive to control your own destiny." 13 A study of 3 types of pharmacist consultation in ambulatory care found that, compared with usual care, more comprehensive pharmacist consultation was associated with a lower risk of death and emergency hospital admission. 14 The highintervention model of pharmacist consultation was associated with a 7.9% reduction in total mortality for new prescriptions filled compared with usual care (voluntary pharmacist consultation) and a 7.8% reduction in mortality risk compared with an intermediate amount of pharmacist consultation with patients. There was also some evidence of a favorable effect of high-intervention pharmacist consultation on the risk of hospitalization in the subgroup analysis for target medications (carbamazepine, digoxin, phenobarbital, phenytoin, procainamide, quinidine, theophylline, or warfarin), a 5.5% risk reduction (P<0.05) and a 3.3% risk reduction in the "high-risk" group (use of nonsteroidal anti-inflammatory drugs and drugs for anxiety, chronic obstructive pulmonary disease, diabetes, epilepsy, and seizure disorders).
In this issue of the Journal, Anderson calculates the direct costs per-patient-per-month (PPPM) of a pharmacist-managed anticoagulation monitoring service in a managed care organization, focusing on patients with atrial fibrillation (AF). Although this is not a new idea, it remains an important one. Examination of the data from 1,355 visits among patients with AF from the National Ambulatory Medical Care Survey showed that oral anticoagulant use increased between 1991 and 2000 but that fewer than half of the patients at high risk for stroke were anticoagulated. 15 Coupled with this apparent unmet need for more anticoagulation therapy among AF patients, examination of the cost benefit of a pharmacist-managed anticoagulation monitoring service found a potential avoidance of costs associated with unplanned clinic visits, emergency room visits, and hospital admissions of $4,073 per person-year ($339 PPPM) in 1988-1993 dollars. 16 Approximately 10 years later, Anderson calculated a $51 PPPM cost for providing the services of an outpatient pharmacist-managed anticoagulation service, including drug costs. He also found favorable effects of the pharmacist anticoagulation service on clinical outcomes as measured by the percentage of international normalized ratio values within each individual patient' s specific INR goal range. 17 In a previous issue of the Journal, Till, Voris, and Horst described the intermediate outcomes in serum lipid values associated with clinical pharmacist intervention in a lipid management clinic. 18 Clinical pharmacists in this VA medical center work in collaborative practice with physicians and other health professionals and assume primary care responsibility for lipid management for patients referred to the clinical pharmacist lipid clinic. This clinical pharmacist intervention includes pharmacist prescribing and dose adjustment of pharmacological therapy. The logic and promise of cost-effectiveness of the "physicians diagnose and pharmacists prescribe" model of health care delivery caused the British government to permit British pharmacists and nurses to prescribe medications beginning in 2003, in partnership with a physician. 19 So-called "collaborative practice" also became a mainstream topic in the United States in 2002 and 2003 and part of government recommendations in a Medicare Payment Advisory Commission (MedPAC) report in June 2002. MedPAC recommended that "the Secretary should assess models for collaborative drug therapy management services in outpatient settings." 20 These roles for clinical pharmacists in collaborative drug therapy management were described more than 5 years before the MedPAC report. In 1997, the American College of Clinical Pharmacy took the position that, in a model drug management relationship, the physician would diagnose the patient and make the initial treatment decision and subsequently authorize the pharmacist to "select, monitor, modify, and discontinue medications as necessary to achieve favorable patient outcomes." 21 In 2000, the Institute for Medicine in its groundbreaking report, To Err Is Human, stated, "Because of the immense variety and complexity of medications now available, it is impossible for nurses or doctors to keep up with all of the information required for safe medication use. The pharmacist has become an essential resource . . . and thus access to his or her expertise must be possible at all times." 22 Data from national surveys of medical groups performed by the Medical Group Management Association and the American Medical Group Association suggest that physicians are increasingly embracing pharmacist consultant services. 23 Aside from the obvious need for collaborative practice to help narrow the chasm of quality in drug therapy management, the fact that physician medical groups are increasingly employing clinical pharmacists in drug therapy management consulting roles suggests a viable business model for collaborative practice. The business model for collaborative practice is encouraging and gives hope to the success that is sought in quality improvement (QI) efforts, aided by self-assessment tools in Bridges to Excellence 24 and in the AMCP Framework for pharmacy services QI. 25 Pasquale et al. found that a pharmacist-physician antibiotic support team produced annualized cost-avoidance savings of $186,720 in year 2000 dollars, before personnel costs. 26 In this issue of the Journal, Arnold, McDonald, Newman, Smith, and Ramirez found that the need for a clinical QI antimicrobial therapy management team appears to persist long term. 27 This is an important finding and one that is consistent with the underlying philosophy of continuous quality improvement. CQI is based upon the "plan-do-check-act" model, not an episodic approach in which an intervention is made and then abandoned. The finding that the need for a QI team in antimicrobial therapy management may persist, over several years and perhaps indefinitely, and that the proportion of interventions with an impact on care processes does not diminish over at least 3 years is of fundamental importance in resource planning. These findings by Arnold et al. reinforce the importance of a long-term view of health services QI-to "hold the gains" achieved from clinical interventions at the same time that new opportunities for QI are discovered. 28

II Reducing the Risk of Fractures-The Options Narrow for Cost-Effective Therapeutic Alternatives
Dissemination of the results of the Women' s Health Initiative (WHI) randomized controlled trial in mid-2002 resulted in a reduction in the pharmacotherapy options to prevent osteo-porosis for many women. While the WHI study results showed a significant reduction in the risk of fractures in women who took hormone therapy (5 fewer cases of hip fracture per 10,000 women treated per year), the higher rate of breast cancer (8 additional cases per 10,000 women treated per year) and cardiovascular events caused researchers from the National Institutes of Health to recommend that women taking combination hormone replacement therapy for osteoporosis should talk to their doctors, and alternatives for osteoporosis prevention should be explored. 29 The benefit-risk balance for estrogen alone may be more favorable, but research continues.
Osteoporosis prevention is an important consideration for women and for men. First-line prevention includes diet and exercise. Calcium, vitamin D, fluoride, and exercise, particularly weight-bearing exercise, are associated with reduction in the rate of loss of bone mineral density (BMD) and/or reduction of fractures, [30][31][32] and research continues on the potential interaction of dietary factors such as protein intake on the favorable effects of calcium and vitamin D intake on BMD. 33 Thiazide diuretics, particularly hydrochlorothiazide, have been associated with modest improvement in spine and hip bone BMD, with significant effects in as early as 6 months for both men and women on both measures. 34 These results from randomized controlled trials are consistent with findings from observational studies of the value of 1 year or more of therapy with thiazide diuretics in reducing the incidence of hip fracture. 35 Drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of osteoporosis include the bisphosphonates alendronate (Fosamax) and risedronate (Actonel), the selective estrogen modulator (SERM) raloxifene (Evista), and calcitonin-salmon (Miacalcin). All have been shown to have a favorable effect on BMD compared with placebo, and all have a drug cost in the range of $750 to $850 per year of therapy, including once-weekly risedronate (35 mg once per week). 36 The recombinant human parathyroid hormone, teriparatide (Forteo), is the fourth type of drug approved by the FDA to treat osteoporosis. Teriparatide increases vertebral BMD and reduces the incidence of vertebral and nonvertebral fractures in patients with osteoporosis but must be given daily by subcutaneous injection, is very expensive (more than $500 per month of therapy), 37 and is associated with antagonistic rather than synergistic activity on BMD when used in combination with the bisphosphonates. 38,39 Vitamin K is approved for the treatment of osteoporosis in Japan and has been proposed for use in combination with other drugs for the management of osteoporosis. 40 While the direct drug cost of the bisphosphonates, raloxifene, and calcitonin-salmon is fairly tightly clustered in the range of $750 to $850 per year of therapy and would appear to have a clear advantage over teriparatide, the cost per osteoporosis-related clinical outcome with these drugs is an important consideration. For example, a 3-year study of 5,445 women aged 70 to 79 years who had osteoporosis and 3,886 women aged 80 years or older without osteoporosis but at least 1 nonskeletal risk factor for hip fracture or low BMD at the femoral neck found that oral risedronate at either 3.5 mg per day or 5.0 mg per day was associated with an incidence of hip fracture of 2.8% compared with 3.9% among patients who received placebo (P = 0.02). 41 For the osteoporosis group only, the incidence of hip fracture was 1.9% versus 3.2% for placebo, an absolute risk reduction of 1.3%, meaning that it would require 231 person-years of risendronate to prevent 1 hip fracture, or about $180,000 of risedronate at discounted pharmacy prices in CY 2004. 42 Also notable was the incidence of hip fracture in the treatment group, 2.8% versus an incidence of 0.6% to 0.8% per year (1.8% to 2.4% over 3 years) for untreated (and unselected) women of the same age. Also, only 50% of the women completed the full 3 years of drug treatment. For the older group with nonskeletal risk factors, the incidence of hip fracture was 4.2% for risedronate compared with 5.1% for placebo. Supplementation with calcium and vitamin D was provided to women in the study.
Watts, Worley, Solis, Doyle, and Sheer report in this issue of the Journal that the bisphosphonates, alendronate and risedronate, are associated with a lower incidence of nonvertebral fractures compared with patients who used calcitonin-salmon and that risedronate may be associated with a slightly lower risk of nonvertebral fractures compared with alendronate. 43 These results were found in 6-month and 12-month periods of observation. One notable finding was that about one half of the patients who received a prescription for one of these 3 study drugs had to be excluded from the analyses due to failure to obtain a refill prescription.
Noncompliance with the bisphosphonates, particularly alendronate, is a well-recognized problem. The finding by Watts, Worley, Solis, Doyle, and Sheer that about one half of patients who receive a prescription for a bisphosphonate discontinue therapy is consistent with the discontinuation rates reported by other researchers. A telephone survey of 812 women members of Kaiser Northern California, with a mean age of 68.7 years, found that between 29% and 35% discontinued therapy after receiving at least 1 prescription for 10 mg alendronate. New upper-GI symptoms ascribed to use of alendronate were reported by 32.7% of users, and the proportion of women discontinuing therapy was 28.6% based on self-report and 34.9% based on refill data. 44 A separate study of 792 health maintenance organization members who started alendronate therapy found a discontinuation rate of 46% in the first few months and a 33% incidence of gastrointestinal (GI) side effects. Both inpatient acid-related costs and outpatient acid-related drug costs were higher in the alendronate group compared with 3 control groups. 45 The effects of bisphosphonates on the GI tract appear to contribute to symptoms that many users find intolerable or unacceptable, and a study reported in 2002 found an incidence of gastric ulcers (greater than or equal to 3 mm) in 6% of 300 patients taking 5 mg per day of risedronate and 12.1% of 297 patients taking alendronate 10 mg per day (P = 0.013). The incidence of ulcers appeared to be unaffected by whether or not the patients were infected with Helicobacter pylori. 46 The bisphosphonates, particularly alendronate, have also been associated with liver toxicity. 47 In addition to the clinical effects, favorable and unfavorable, of drugs used to reduce the risk of osteoporotic-related fractures, some of these drugs have withered under scrutiny of costeffectiveness. In December 2003, a committee at the National Institute for Clinical Excellence (NICE) in the United Kingdom concluded that raloxifene "is not cost-effective treatment for postmenopausal osteoporosis." 48 The bisphosphonates, alendronate and risedronate, were approved by the committee but only for use in patients who have already suffered an osteoporosis-related fracture. The committee acknowledged that raloxifene "is effective in preventing vertebral fractures in women with osteoporosis and severe osteoporosis" but found it to have a higher (unfavorable) cost-effective ratio compared with other drugs in the osteoporosis class. 49